Kalter Nechama, Fuster-García Carla, Silva Alfredo, Ronco-Díaz Víctor, Roncelli Stefano, Turchiano Giandomenico, Gorodkin Jan, Cathomen Toni, Benabdellah Karim, Lee Ciaran, Hendel Ayal
The Institute for Advanced Materials and Nanotechnology, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
Mol Ther Nucleic Acids. 2025 Jul 17;36(3):102636. doi: 10.1016/j.omtn.2025.102636. eCollection 2025 Sep 9.
Targeted nucleases, primarily CRISPR-Cas-based systems, have revolutionized genome editing by enabling precise modification of target genes or transcripts. Many pre-clinical and clinical studies leverage this technology to develop treatments for human diseases; however, substantial off-target genotoxicity concerns delay its clinical translation. Despite the development of a wide array of tools, assays, and technologies aimed at identifying and quantifying off-target effects, the absence of standardized guidelines leads to inconsistent practices across studies. This review highlights the key challenges and potential solutions in ensuring the safety of gene editing studies for therapeutic applications, focusing on gRNA design, off-target sites prediction, and off-target activity measurement.
靶向核酸酶，主要是基于CRISPR-Cas的系统，通过能够对靶基因或转录本进行精确修饰，彻底改变了基因组编辑。许多临床前和临床研究利用这项技术开发人类疾病的治疗方法；然而，对脱靶基因毒性的严重担忧延缓了其临床转化。尽管已经开发出了大量旨在识别和量化脱靶效应的工具、检测方法和技术，但缺乏标准化指南导致各研究之间的做法不一致。本综述重点介绍了在确保基因编辑治疗应用研究安全性方面的关键挑战和潜在解决方案，重点关注gRNA设计、脱靶位点预测和脱靶活性测量。
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